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Immunogenetics

, Volume 68, Issue 2, pp 145–155 | Cite as

HIV-1 gp140 epitope recognition is influenced by immunoglobulin DH gene segment sequence

  • Yuge Wang
  • Pratibha Kapoor
  • Robert Parks
  • Aaron Silva-Sanchez
  • S. Munir Alam
  • Laurent Verkoczy
  • Hua-Xin Liao
  • Yingxin Zhuang
  • Peter Burrows
  • Michael Levinson
  • Ada Elgavish
  • Xiangqin Cui
  • Barton F. Haynes
  • Harry SchroederJrEmail author
Original Article

Abstract

Complementarity Determining Region 3 of the immunoglobulin (Ig) H chain (CDR-H3) lies at the center of the antigen-binding site where it often plays a decisive role in antigen recognition and binding. Amino acids encoded by the diversity (DH) gene segment are the main component of CDR-H3. Each DH has the potential to rearrange into one of six DH reading frames (RFs), each of which exhibits a characteristic amino acid hydrophobicity signature that has been conserved among jawed vertebrates by natural selection. A preference for use of RF1 promotes the incorporation of tyrosine into CDR-H3 while suppressing the inclusion of hydrophobic or charged amino acids. To test the hypothesis that these evolutionary constraints on DH sequence influence epitope recognition, we used mice with a single DH that has been altered to preferentially use RF2 or inverted RF1. B cells in these mice produce a CDR-H3 repertoire that is enriched for valine or arginine in place of tyrosine. We serially immunized this panel of mice with gp140 from HIV-1 JR-FL isolate and then used enzyme-linked immunosorbent assay (ELISA) or peptide microarray to assess antibody binding to key or overlapping HIV-1 envelope epitopes. By ELISA, serum reactivity to key epitopes varied by DH sequence. By microarray, sera with Ig CDR-H3s enriched for arginine bound to linear peptides with a greater range of hydrophobicity but had a lower intensity of binding than sera containing Ig CDR-H3s enriched for tyrosine or valine. We conclude that patterns of epitope recognition and binding can be heavily influenced by DH germ line sequence. This may help explain why antibodies in HIV-infected patients must undergo extensive somatic mutation in order to bind to specific viral epitopes and achieve neutralization.

Keywords

Epitope Immunoglobulin DH gene Complementarity determining region (CDR-H3) HIV-1 envelope protein 

Notes

Acknowledgments

The work was supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health Grants AI07051, AI48115, and AI090742.

Supplementary material

251_2015_890_MOESM1_ESM.xlsx (102 kb)
ESM 1 (XLSX 101 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Yuge Wang
    • 1
  • Pratibha Kapoor
    • 3
  • Robert Parks
    • 4
  • Aaron Silva-Sanchez
    • 1
    • 2
  • S. Munir Alam
    • 4
  • Laurent Verkoczy
    • 4
  • Hua-Xin Liao
    • 4
  • Yingxin Zhuang
    • 2
  • Peter Burrows
    • 1
  • Michael Levinson
    • 1
  • Ada Elgavish
    • 2
  • Xiangqin Cui
    • 3
  • Barton F. Haynes
    • 4
  • Harry SchroederJr
    • 1
    • 2
  1. 1.Department of MicrobiologyThe University of Alabama at BirminghamBirminghamUSA
  2. 2.Department of MedicineThe University of Alabama at BirminghamBirminghamUSA
  3. 3.Department of BiostatisticsThe University of Alabama at BirminghamBirminghamUSA
  4. 4.Duke Human Vaccine InstituteDuke University School of MedicineDurhamUSA

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